ABSTRACT Genital tract infection with Neisseria gonorrhoeae (gonorrhea) does not induce a state of specific protective immunity and it can be acquired repeatedly. Despite public health measures, the disease persists at an unacceptably high frequency; there is no vaccine against it, and resistance even to the latest generations of antibiotics continues to emerge. Recent findings have revealed that N. gonorrhoeae subverts the immune system for its own benefit by eliciting innate responses that it can survive and by suppressing specific adaptive responses that would eliminate it. However, this induced immunosuppression can be reversed by treatments that effectively redirect the immune response against N. gonorrhoeae. Proof-of-principle has been established for a novel strategy of prophylaxis against genital gonococcal infection using a mouse model that is accepted as the only currently available animal model. The current vaccine prototype, GvaX12 (a combinatorial formulation of our proprietary sustained-release nanoparticulate interleukin-12 and gonococcal outer membrane vesicles) induces anti-gonococcal T-cell and antibody responses, and generates protection against homologous and heterologous strains for up to 6 months. In this Phase II application, we will define, optimize, and validate a vaccination regimen including route, aiming for intranasal administration. We will determine the basis of cross-protection against diverse strains of naturally occurring N. gonorrhoeae, and begin preliminary pharmacokinetics and toxicology studies in preparation for subsequent toxicological testing in nonhuman primates. Along with the preclinical data, toxicology results and future plans will be incorporated into a briefing package that will be submitted to the FDA in a request for a Type C Meeting.